16
Soft Tissue Sarcomas
Marc P. Hickeson
Soft tissue sarcomas are a heterogeneous group of malignant neo- plasms of mesenchymal origin. They account for approximately 1% of all cancer diagnoses and 7% of pediatric malignancies (1,2). Just over half of these patients eventually succumb as a result of the disease. Soft tissue sarcomas typically present as asymptomatic large masses within the retroperitoneum or the proximal lower limbs but can also affect other sites of the body. In adults, the most common histologic origins are liposarcomas (21%), malignant fibrous histiocytomas (MFHs) (20%), leiomyosarcomas (20%), fibrosarcomas (11%), and tendosyn- ovial sarcomas (10%) (3). In children, rhabdomyosarcoma comprise approximately 70% of the soft tissue sarcomas (3). Despite this highly variable histopathologic origin, the three negative predictive factors at the time of initial diagnosis for disease-free survival are primary site in the superficial trunk or in the limbs, high tumor grade, and large tumor size, rather than the histologic origin (4).
Roles of PET
For soft tissue sarcomas, positron emission tomography (PET) has been shown to be useful in the following capacities:
1. Evaluation of the primary lesion 2. Staging of the disease
3. Monitoring therapy and detection of recurrence 4. Prognostic information
Evaluation of the Primary Lesion
Correct diagnosis of the soft tissue sarcoma is important because treat- ment is effective for many if diagnosed early. However, benign soft tissue masses can appear very similar to soft tissue sarcoma on physi- cal examination and radiologic investigation. The most specific method to diagnose sarcoma is by biopsy. An alternative noninvasive method is PET with fluorine-18 (18F)-fluorodeoxyglucose (FDG), which has
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been used for the initial diagnosis and grading of soft tissue sarcomas in several series (5–14). On a meta-analysis with a total of 441 lesions (15), the sensitivity and specificity were 92% and 73% by qualitative evaluation, 87% and 79% for a standard uptake value (SUV) of 2.0, and 70% and 87% for SUV 3.0 to diagnose malignant versus benign lesions.
The sensitivity of FDG-PET is higher for high-grade malignant lesions than for low-grade lesions (5,16). All intermediate/high-grade sarco- mas were detected with qualitative visualization as compared to 74%
of low-grade sarcomas and 39% of benign lesions on a meta-analysis (15). Another meta-analysis including 341 patients with soft tissue sarcomas reported sensitivity and specificity of 88% and 86%, respec- tively, and showed that FDG-PET can discriminate low- and high- grade sarcomas based on the SUV (17). The most common cause for false-negative studies is low-grade sarcoma with low FDG uptake;
the most common cause for false-positive studies is inflammation.
Fluorodeoxyglucose-PET may also be useful as noninvasive screening modality for malignant transformation of premalignant lesions.
The kinetics of FDG uptake differ in benign and malignant tumors.
Hamberg et al. (18) reported that malignant tumors reach maximal uptake of FDG approximately 5 hours after the time of injection.
However, benign lesions reach a maximum much earlier, within 30 minutes after FDG injection (12). It is unclear why malignant and benign lesions demonstrate different uptake patterns over time.
Although it is well known that an increased number of glucose transporters are present in tumor cells, this does not account for FDG trapping. Hexokinase and glucose-6-phosphatase mediate the phos- phorylation and dephosphorylation, respectively, of FDG. It has been reported that the rate of dephosphorylation of FDG-6-phosphate is responsible for the difference in kinetics in malignant and benign lesions (19,20). Unless FDG-6-phosphate is dephosphorylated to FDG by glucose-6-phosphatase, it is unable to leave the cell. Lodge et al. (12) reported an improved differentiation of high-grade sarcomas from benign lesions using a SUV measured at 4 hours postinjection as com- pared to earlier after FDG injection.
Another approach is to obtain dual-time point imaging to differen- tiate benign from malignant lesions (21–24). This method has been par- ticularly helpful for lesions associated with low-grade increased FDG activity. In this approach, the lesion’s SUV is measured at two differ- ent time points after FDG injection. Malignant lesions tend to increase in intensity between the two scans, whereas benign lesions tend to remain stable or decrease slightly in intensity. This technique has been validated for the evaluation of solitary pulmonary nodules (22–24).
This difference of kinetics of FDG uptake has also been observed for soft tissue sarcomas (12).
Computed tomography (CT) and magnetic resonance imaging (MRI) have an important role in determining the site of the disease and its local extent. The most specific method for the diagnosis and grading of the lesion is by biopsy of the mass. Although the site and extent of the lesion can be accurately delineated with anatomic imaging modal- ities, these tumors are sometimes highly heterogeneous. For this
reason, the portion of the tumor with the highest grade may be missed on biopsy of only a small region. Hain et al. (25) have reported that in malignant masses the site that was the most likely to be malignant on FDG-PET was found to be representative of the most malignant site on the whole mass histology. Fluorodeoxyglucose-PET can be used to direct preoperative biopsy of soft tissue mass and to prevent the under- estimation of the grade of the sarcoma that would result in suboptimal management of the disease (25,26). The availability of PET-CT imaging further enhances the usefulness of this application by providing the precise CT anatomic localization of the metabolic abnormalities on PET.
Staging for Metastases
Magnetic resonance imaging, CT scan, and FDG-PET imaging have complementary roles in staging soft tissue sarcomas (Table 16.1). Lucas et al. (11) reported sensitivity and specificity of 86.7% and 100%, respec- tively, with FDG-PET and sensitivity and specificity of 100% and 96.4%, respectively, with CT for the detection of pulmonary metastases.
However, an additional 13 unsuspected sites of metastases were demonstrated on FDG-PET. One advantage of FDG-PET over other imaging modalities is that all organ systems can be visualized in a single examination. Johnson et al. (27) reported that FDG-PET correctly diagnosed or excluded local recurrence and distant metastases in 33 patients. In some cases, FDG-PET detected metastases before they were present on CT scan and MRI. These data suggest that FDG-PET is useful for staging for distant metastases and offers complementary information provided by anatomic imaging modalities.
Monitoring Therapy and Detection of Recurrence
Approximately 10% to 15% of patients develop local recurrence and 35% to 45% develop distant metastases despite adequate treatment.
Table 16.1. American Joint Committee on Cancer (AJCC) staging system for soft tissue sarcoma
Stage Description
IA Low-grade sarcoma; tumor £5 cm; no nodal or systemic metastases (G1T1N0M0)
IB Low-grade sarcoma; tumor >5 cm; no nodal or systemic metastases (G1T2N0M0)
IIA Moderate-grade sarcoma; tumor £5 cm; no nodal or systemic metastases (G2T1N0M0)
IIB Moderate-grade sarcoma; tumor >5 cm; no nodal or systemic metastases (G2T2N0M0)
IIIA High-grade sarcoma; tumor £5 cm; no nodal or systemic metastases (G3T1N0M0)
IIIB High-grade sarcoma; tumor >5 cm; no nodal or systemic metastases (G3T2N0M0)
IVA Any grade sarcoma; any tumor size; with regional node metastases;
no systemic metastases (any G, any T, N1M0)
IV Any grade sarcoma; any tumor size; any nodal status; with systemic metastases (any G, any T, any N, M1)
Early detection of recurrence allows a larger variety of treatment options and results in better prognosis than late detection of recurrence.
Therefore, early detection of recurrence is important for the treatment of sarcomas.
There has been a significant evolution in the treatment of soft tissue sarcoma. For aggressive tumors, surgical resection is the method of choice of local control. For sarcomas involving the limbs, limb- sparing procedures can be appropriately performed by chemotherapy in the neoadjuvant (presurgical) setting. The primary objective is tumor eradication. However, the response to therapy varies consider- ably with different tumors. Identification of resistant or nonrespond- ing tumors early or immediately after initiation of therapy would be most advantageous, so that an alternative, potentially more effective, treatment can be instituted in a timely manner. Toxicities from inef- fective therapy can also be prevented. Unlike anatomic imaging modalities, which assess tumor response by size criteria, PET assesses the metabolic activity of tumors. Studies have shown that therapy- induced anatomic changes lag behind metabolic changes of the tumor (28).
One specific example that FDG-PET has demonstrated its utility for early prediction of response to therapy is with the treatment of gas- trointestinal intestinal stromal tumors (GISTs), which are tumors of mesenchymal origin arising from the gastrointestinal tract. A signifi- cant percentage of these tumors have an exceptional response to the tyrosine kinase inhibitor, imatinib mesylate (Gleevec/Glivec). Fluo- rodeoxyglucose-PET has been shown to be an early indicator of tumor response to treatment (Figs. 16.1 to 16.3) (29). In all responders, a sig- nificant decrease of FDG uptake was observed as early as 24 hours after the administration of a single dose of Gleevec. Subsequent studies have indicated that FDG-PET is the imaging modality of choice for early
A B
Figure 16.1. Patient has a tenosynovial cell sarcoma in the left knee, which is demonstrated on the baseline fluorodeoxyglucose–positron emission tomogra- phy (FDG-PET) scan (A). The posttherapy FDG-PET scan (B) demonstrated a complete metabolic response to therapy.
A B C
T ANT SUV
1 POS 728-732
S HEAD SUV C HEAD SUV
RIGHT LEFT
RIGHT LEFT
ANT POS
1 FOOT 334-338 1 FOOT 282-286
Figure 16.2. Patient with gastrointestinal stroma tumor of the stomach who had undergone FDG-PET study after chemotherapy. The transaxial (A), sagittal (B), and coronal images (C) are shown and demonstrate a large mass with no evidence of FDG metabolism (arrows) with the exception of a focus of hypermetabolism at its stalk (arrowheads), which was proven to be residual tumor.
A
B
Figure 16.3. Partial metabolic response in this patient with history of gastrointestinal stromal tumor of the rectum who had undergone FDG-PET study prior to (A, narrow arrows) and 3 weeks after initia- tion of therapy (B, wide arrows).
prediction of response to therapy for a patient with GIST treated with Gleevec (30–32).
The metabolic response of tumor from therapy can be defined using the European Organization for Research and Treatment of Cancer (EORTC) criteria (Table 16.2) (33).
Hain et al. (34) studied the findings of 16 patients with amputation in either the upper or lower limb on FDG-PET. Diffuse hypermetabo- lism at the amputation stump up to 18 months postsurgery is a common finding. However, focal hypermetabolism may be associated with a pressure area if there is clinical evidence of skin breakdown at that site. However, if there is no evidence of localized skin breakdown at the site of focal hypermetabolism, then the finding indicates a recur- rence, and a skin biopsy is indicated. Kole et al. (35) have also reported a 93% sensitivity of FDG-PET for the detection of recurrence of soft tissue sarcomas in 14 patients.
Prognostic Information
A noninvasive method to determine tumor regional glucose metabo- lism is with FDG-PET. Eary et al. (36) reported that FDG-PET provides independent prognostic information in a retrospective analysis of 209 patients with sarcomas. They have shown that the risk of death increases by approximately 60% for each doubling of the maximal base- line lesion SUV. Schuetze et al. (37) have demonstrated that soft tissue sarcomas with a pretreatment SUV of greater than 6.0 are associated with a higher risk of recurrence and of mortality than those with SUV of less than 6.0. Another negative prognostic finding provided by FDG- PET is lack of reduction in SUV of the lesion with therapy (Fig. 16.4) (37). In general, FDG tumor activity is positively associated with the metabolic activity, and tumor metabolic activity is positively associated with aggressiveness. Aggressive tumors have a worse prognosis than those with less aggressive histology.
Table 16.2. Tumor response using FDG-PET with the European Organization for Research and Treatment of Cancer (EORTC) criteria
Response Definition
Progressive Increase in FDG tumor SUV of equal or greater metabolic disease than 25% within the tumor region as compared to
the baseline study or appearance of new FDG uptake in metastatic lesions
Stable disease Increase in tumor FDG uptake of less than 25% or a decrease of less than 15% of FDG uptake within the tumor region as compared to the baseline study
Partial metabolic Reduction of at least 15% of FDG uptake within the response tumor as compared to the baseline study
Complete metabolic Complete resolution of FDG uptake within the
response tumor
A
B
Figure 16.4. Evidence of progression in this patient with an aggressive metastatic sarcoma of the left foot who had undergone FDG-PET study prior to (A) and after completing chemotherapy (B). The base- line SUV was 13.9; this increased to 18.2 on the posttherapy scan, which indicates a poor prognosis.
Conclusion
Positron emission tomography with 18F-fluorodeoxyglucose has been shown to have potential value in the evaluation of primary malignant lesions, for staging, for the response to treatment and detection of recurrence, and for prognostic information.
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